Method of preparing Alogliptin

A compound and reaction technology, applied in the field of preparation of alogliptin and its benzoate and its intermediates, can solve problems such as relatively expensive starting raw materials, unfavorable industrial production, and no obvious cost advantage, so as to avoid Use of high boiling point solvents and highly dangerous reagents, simplified operation, and improved yield

Inactive Publication Date: 2014-03-26
CHONGQING PHARMA RES INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Disadvantages: the reaction line is longer, the price of starting materials is more expensive, and highly toxic reagents such as phosphorus oxychloride are used, so there is no cost advantage
[0019] The yield of the first two steps of the method is 51% to 54%, which is all improved compared with the reaction route 1, but there is no obvious cost advantage
[0020] In the prior art mentioned above, either high boiling point solvents such as N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone and dangerous substance NaH are used, which is not conducive to industrial production; or The use of highly toxic reagents such as methyl iodide and phosphorus oxychloride increases the pressure on environmental protection; or the raw materials are expensive and the route is long, which increases the cost
Clearly, there are significant limitations in existing synthetic methods

Method used

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  • Method of preparing Alogliptin
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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0059] Example 1 Preparation of 2-(6-chloro-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-benzonitrile (Ⅴ)

[0060] 1a) Suspend 6-chlorouracil (50g) in tetrahydrofuran (300ml), add N,N-diisopropylethylamine (80ml), then dropwise add 2-cyanobenzyl bromide (66.3g) Tetrahydrofuran (100ml) solution. The mixed solution was stirred and reacted at 20-65°C, a large amount of solids precipitated out, and the reaction was detected by thin-layer chromatography. After the reaction was complete, the solid formed by the reaction was filtered, washed with tetrahydrofuran (30ml), and then poured into 100ml of water and stirred for 5 minutes. After filtering, washing with water and drying under reduced pressure, 50 g of 2-(6-chloro-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-benzonitrile (Ⅴ) was obtained. The previous tetrahydrofuran mother liquor was concentrated and then recrystallized with tetrahydrofuran to obtain another 15 g of the target product, with a total yield of 72.8%.

[00...

Embodiment 2

[0062] Example 2 Preparation of 2-(6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)benzonitrile (IV)

[0063] 2a) Suspend compound V (5.22g) in tetrahydrofuran (40ml), add methanol (3ml) and triphenylphosphine (7.77g) in sequence, add diisopropyl azodicarboxylate dropwise to the reaction solution at room temperature Ester (6.02g), the mixture was reacted at room temperature for 3 hours, and the reaction was complete as detected by thin layer chromatography. The reaction solution was concentrated under reduced pressure, and the residue was recrystallized from a mixed solution of methanol and methyl tert-butyl ether to obtain 2-(6-chloro-3-methyl-2,4-dioxo-3,4-dihydro -2H-pyrimidin-1-ylmethyl)benzonitrile (IV) 4g, the mother liquor was concentrated and subjected to silica gel column chromatography (gradient elution with petroleum ether-ethyl acetate as the eluent) to obtain 1.2g of the target product, The total reaction yield is 94.5%.

[0064] 2b) Suspend comp...

Embodiment 3

[0066] Example 3 2-{6-[3(R)-amino-piperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidine-1- Preparation of methyl}-benzonitrile benzoate (Ⅰ)

[0067] 3a) Compound IV (5.2g), sodium bicarbonate (4.2g) and (R)-3-amino-piperidine dihydrochloride (3.48g) were suspended in acetonitrile (200ml), and refluxed for 14 hours. Thin-layer chromatography detected that the reaction was complete, the reaction solution was lowered to room temperature, filtered to remove most of the sodium bicarbonate, the mother liquor was concentrated, the residue was dissolved in dichloromethane, washed with water, dried over anhydrous sodium sulfate for half an hour, and filtered to remove sodium sulfate. Add benzoic acid (4 g) to the filtrate, stir at room temperature for 2 hours, concentrate under reduced pressure, dissolve the residue with a small amount of methanol, and then add diethyl ether or methyl tert-butyl ether to precipitate an off-white solid. The white solid was filtered off and recry...

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PUM

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Abstract

The invention relates to Alogliptin, benzoate thereof and a preparation method of an intermediate of the Alogliptin. The method comprises the following steps: alkylating 6-chlorouracil by using 2-(bromomethyl)benzonitrile on the basis of a tetrahydrofuran solvent and the catalysis of alkali to generate N-benzyluracil derivatives, and further alkylating by using methanol through a Mitsunobu reaction to obtain 1,3-disubstituted uracil (intermediate). The method does not need a NaH risk agent and highly toxic agent methyl iodide in the prior art, and is safe and environment-friendly.

Description

[0001] field of invention [0002] The invention belongs to the field of medicinal chemistry, and in particular relates to alogliptin, a benzoate salt thereof and a preparation method of an intermediate thereof. Background technique [0003] Alogliptin benzoate (alogliptin benzoate) is a dipeptidyl peptidase-IV (DPP-IV) inhibitor developed by Takeda Corporation of Japan and launched in September 2011 for the treatment of type 2 diabetes. Alogliptin Benzoate Chemical name 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo- 1(2H)-Pyrimidinyl]methyl]benzonitrile benzoate. [0004] Diabetes affects millions of people worldwide and is considered one of the major threats to human mortality in the 21st century. In 2006, the World Health Organization (WHO) estimated that more than 180 million people worldwide had diabetes, a number that was predicted to double by 2030. Over time, uncontrolled diabetes can damage body systems, including the heart, blood vessels, eye...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/553C07D401/04
CPCC07D239/553C07D401/04
Inventor 邹春兰邓杰张强谢守全王学瑞蔡中文叶文润
Owner CHONGQING PHARMA RES INST
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